Efficacy, Biodistribution, and Pharmacokinetics of CD22-Targeted Pegylated Liposomal Doxorubicin in a B-cell Non-Hodgkin's Lymphoma Xenograft Mouse Model

• Published in: Clinical cancer research 2010-05, Vol.16 (10), p.2760-2768
• Main Authors: TUSCANO, Joseph M, MARTIN, Shiloh M, YUNPENG MA, ZAMBONI, William, O'DONNELL, Robert T
• Format: Article
• Language: English
• Subjects: Animals; Antibodies, Monoclonal - administration & dosage; Antibodies, Monoclonal - pharmacokinetics; Antineoplastic agents; Antineoplastic Agents - administration & dosage; Antineoplastic Agents - pharmacokinetics; Biological and medical sciences; Doxorubicin - administration & dosage; Doxorubicin - analogs & derivatives; Doxorubicin - pharmacokinetics; Drug Delivery Systems; Female; Hematologic and hematopoietic diseases; Humans; Immunotherapy - methods; Leukemias. Malignant lymphomas. Malignant reticulosis. Myelofibrosis; Liposomes; Lymphoma, B-Cell - drug therapy; Medical sciences; Mice; Mice, Nude; Pharmacology. Drug treatments; Polyethylene Glycols - administration & dosage; Polyethylene Glycols - pharmacokinetics; Sialic Acid Binding Ig-like Lectin 2 - immunology; Tissue Distribution; Xenograft Model Antitumor Assays
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-09-3199

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). 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. 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. 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.