Efficacy, biodistribution, and pharmacokinetics of CD22-targeted pegylated liposomal doxorubicin in a B-cell non-Hodgkin's lymphoma xenograft mouse model.

Abstract

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.

• Authors: Joseph M Tuscano, Shiloh M Martin, Yunpeng Ma, William Zamboni, Robert T O'Donnell
• Journal: Clinical cancer research : an official journal of the American Association for Cancer Research (Clin Cancer Res) Vol. 16 Issue 10 Pg. 2760-8 (May 15 2010) ISSN: 1557-3265 [Electronic] United States
• PMID: 20460479 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)
• Copyright: Copyright (c) 2010 AACR.

Chemical References

• Antibodies, Monoclonal
• Antineoplastic Agents
• Liposomes
• Sialic Acid Binding Ig-like Lectin 2
• liposomal doxorubicin
• Polyethylene Glycols
• Doxorubicin

Topics

• Animals
• Antibodies, Monoclonal (administration & dosage, pharmacokinetics)
• Antineoplastic Agents (administration & dosage, pharmacokinetics)
• Doxorubicin (administration & dosage, analogs & derivatives, pharmacokinetics)
• Drug Delivery Systems
• Female
• Humans
• Immunotherapy (methods)
• Liposomes
• Lymphoma, B-Cell (drug therapy)
• Mice
• Mice, Nude
• Polyethylene Glycols (administration & dosage, pharmacokinetics)
• Sialic Acid Binding Ig-like Lectin 2 (immunology)
• Tissue Distribution
• Xenograft Model Antitumor Assays