Journal
CLINICAL CANCER RESEARCH
Volume 16, Issue 10, Pages 2760-2768Publisher
AMER ASSOC CANCER RESEARCH
DOI: 10.1158/1078-0432.CCR-09-3199
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Funding
- Veterans Administration Merit Award
- Leukemia and Lymphoma Society Translational Research Award
- Schwedler Family Foundation
- The deLeuze Endowment for the Nontoxic Cure of Lymphoma
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Purpose: Non-Hodgkin's lymphoma (NHL) is the sixth most common cause of cancer death in the U. S. Pegylated liposomal doxorubicin (PLD) is a liposomal form of doxorubicin (DXR) that causes less toxicity than does free DXR. To further enhance efficacy and decrease toxicity, we conjugated HB22.7, an anti-CD22 monoclonal antibody to PLD, thus creating CD22-targeted immunoliposomal PLD (IL-PLD). Experimental Design: In vitro cytotoxicity of IL-PLD and PLD was assessed in CD22-positive and CD22-negative cell lines. Biodistribution, myelotoxicity, and plasma pharmacokinetics were measured in NHL xenograft-bearing mice treated with IL-PLD or PLD. Survival, tumor volume, and toxicity (WBC counts, body weights) were assessed in mice receiving a single dose (8, 12, or 16 mg DXR/kg) or three doses (8 mg DXR/kg/dose) of IL-PLD; controls were PLD, free DXR, PLD plus unconjugated HB22.7, IL-null (HB22.7-conjugated empty liposome), and nontreated mice. Results: IL-PLD improved cytotoxicity over PLD only in CD22-positive cells. IL-PLD displayed similar pharmacokinetics and toxicities as PLD. Tumor DXR accumulation was greater and tumor/normal tissue ratios were similar (spleen) or greater (kidney, lung, and liver) in mice treated with IL-PLD versus PLD. IL-PLD reduced tumor volume more effectively than PLD at all doses; the three-dose regimen was superior. The three-dose regimen was used in confirmatory studies, which showed that IL-PLD produced significantly greater tumor volume reduction and enhanced survival versus PLD. Conclusion: IL-PLD has increased efficacy without increased toxicity compared with PLD. This suggests that IL-PLD may be an improved form of DXR-based therapy of NHL. Clin Cancer Res; 16(10); 2760-8. (C) 2010 AACR.
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