title: Anti-HER2 immunoliposomes: enhanced efficacy attributable to targeted delivery.
abstract: OBJECTIVE
  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.
  
  
  METHODS
  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.
authors.affiliation: Division of Hematology/Oncology, University of California, San Francisco, San Francisco, California 94143, USA. jpark@cc.ucsf.edu
authors.forename: John W
authors.initials: JW
authors.lastname: Park
authors.forename: Keelung
authors.initials: K
authors.lastname: Hong
authors.forename: Dmitri B
authors.initials: DB
authors.lastname: Kirpotin
authors.forename: Gail
authors.initials: G
authors.lastname: Colbern
authors.forename: Refaat
authors.initials: R
authors.lastname: Shalaby
authors.forename: Jose
authors.initials: J
authors.lastname: Baselga
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Shao
authors.forename: Ulrik B
authors.initials: UB
authors.lastname: Nielsen
authors.forename: James D
authors.initials: JD
authors.lastname: Marks
authors.forename: Dan
authors.initials: D
authors.lastname: Moore
authors.forename: Demetrios
authors.initials: D
authors.lastname: Papahadjopoulos
authors.forename: Christopher C
authors.initials: CC
authors.lastname: Benz
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000276:immunology*; D000970:Antineoplastic Agents / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D019540:Area Under Curve; D001943:Breast Neoplasms / Q000188:drug therapy / Q000473:pathology; D004305:Dose-Response Relationship, Drug; D004317:Doxorubicin / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use*; D016503:Drug Delivery Systems / Q000379:methods; D004357:Drug Synergism; D006801:Humans; D007128:Immunoglobulin Fragments / Q000008:administration & dosage / Q000276:immunology; D008081:Liposomes / Q000493:pharmacokinetics; D008325:Mammary Neoplasms, Experimental / Q000188:drug therapy / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D051381:Rats; D017207:Rats, Sprague-Dawley; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology*; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured; D023041:Xenograft Model Antitumor Assays
chemical_list: D000911:Antibodies, Monoclonal; D000970:Antineoplastic Agents; D004317:Doxorubicin; D007128:Immunoglobulin Fragments; D008081:Liposomes; D018719:Erb-b2 Receptor Tyrosine Kinases