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


METHODS
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.


CONCLUSIONS
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.
Tuscano
Joseph M
JM
Division of Hematology and Oncology, Department of Internal Medicine, University of California, Davis, CA, USA. joseph.tuscano@ucdmc.ucdavis.edu
Martin
Shiloh M
SM
Ma
Yunpeng
Y
Zamboni
William
W
O'Donnell
Robert T
RT
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics*; D004317:Doxorubicin / Q000008:administration & dosage / Q000031:analogs & derivatives* / Q000493:pharmacokinetics; D016503:Drug Delivery Systems; D005260:Female; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D008081:Liposomes; D016393:Lymphoma, B-Cell / Q000188:drug therapy*; D051379:Mice; D008819:Mice, Nude; D011092:Polyethylene Glycols / Q000008:administration & dosage / Q000493:pharmacokinetics*; D051918:Sialic Acid Binding Ig-like Lectin 2 / Q000276:immunology*; D014018:Tissue Distribution; D023041:Xenograft Model Antitumor Assays
D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D008081:Liposomes; D051918:Sialic Acid Binding Ig-like Lectin 2; C506643:liposomal doxorubicin; D011092:Polyethylene Glycols; D004317:Doxorubicin