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Anti-HER2 Immunoliposomes

Enhanced Efficacy Attributable to Targeted Delivery¹

Division of Hematology/Oncology [J. W. P., C. C. B.] and Department of Anesthesia [U. B. N., J. D. M.], University of California, San Francisco, San Francisco, California 94143; California Pacific Medical Center Research Institute, San Francisco, California 94115 [K. H., D. B. K., G, C., R, S., Y. S., D. M., D. P.]; Memorial Sloan-Kettering Cancer Center, New York, New York [J. B.]

Purpose: Anti-HER2 immunoliposomes combine the tumor-targeting of certain anti-HER2 monoclonal antibodies (MAbs) with the pharmacokinetic and drug delivery capabilities of sterically stabilized liposomes. We previously showed that anti-HER2 immunoliposomes bind efficiently to and internalize in HER2-overexpressing cells in vitro, resulting in intracellular drug delivery.

Experimental Design: Here we describe the pharmacokinetics and therapeutic efficacy of anti-HER2 immunoliposomes containing doxorubicin (dox) in a series of animal models.

Results: Immunoliposomes displayed long circulation that was identical to that of sterically stabilized liposomes in single- and multiple-dose studies in normal rats. Anti-HER2 immunoliposome-dox produced marked therapeutic results in four different HER2-overexpressing tumor xenograft models, including growth inhibition, regression, and cures. These results demonstrated that encapsulation of dox in anti-HER2 immunoliposomes greatly increased its therapeutic index, both by increasing antitumor efficacy and by reducing systemic toxicity. Immunoliposome-dox was significantly superior to all other treatment conditions tested, including free dox, liposomal dox, and anti-HER2 MAb (trastuzumab). When compared with liposomal dox in eight separate therapy studies in HER2-overexpressing models, immunoliposome delivery produced significantly superior antitumor efficacy in each study (P < 0.0001 to 0.04). Anti-HER2 immunoliposome-dox containing either recombinant human MAb HER2-Fab' or scFv C6.5 yielded comparable therapeutic efficacy. Cure rates for immunoliposome-dox reached 50% (11 of 21) with optimized immunoliposomes and Matrigel-free tumors and overall was 16% (18 of 115) versus no cures (0 of 124) with free dox or liposomal dox. Finally, anti-HER2 immunoliposome-dox was also superior to combinations consisting of free MAb plus free dox or free MAb plus liposomal dox.

Conclusions: Anti-HER2 immunoliposomes produced enhanced antitumor efficacy via targeted delivery.

Commentary

The Potential of Drug-carrying Immunoliposomes as Anticancer Agents : Commentary re: J. W. Park et al., Anti-HER2 Immunoliposomes: Enhanced Efficacy due to Targeted Delivery. Clin. Cancer Res., 8: 1172–1181, 2002.

Doris R. Siwak, Ana M. Tari, and Gabriel Lopez-Berestein
Clin. Cancer Res. 2002 8: 955-956. [Full Text] [PDF]

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