title: Modulation of cancer cell survival pathways using multivalent liposomal therapeutic antibody constructs.
abstract: Various methods have been explored to enhance antibody-based cancer therapy. The use of multivalent antibodies or fragments against tumor antigens has generated a great deal of interest, as various cellular signals, including induction of apoptosis, inhibition of cell growth/survival, or internalization of the surface molecules, can be triggered or enhanced on extensive cross-linking of the target/antibody complex by the multivalent form of the antibody. The goal of the studies reported here was to develop multivalent antibody constructs via grafting of antibody molecules onto liposome membranes to enhance antibody activity. Using trastuzumab and rituximab as examples, up to a 25-fold increase in the antibody potency in cell viability assay was observed when the antibodies were presented in the multivalent liposome formulation. Key cell survival signaling molecules, such as phosphorylated Akt and phosphorylated p65 nuclear factor-kappaB, were down-regulated on treatment with multivalent liposomal trastuzumab and liposomal rituximab, respectively. Potent in vivo antitumor activity was shown for liposomal trastuzumab. The data presented here showed the potential of liposome technology to enhance the therapeutic effect of antibodies via a mechanism that modulates cell survival through clustering of the target/antibody complex.
authors.affiliation: Department of Pharmacy, Faculty of Science, National University of Singapore, 18 Science Drive 4, Singapore 117543, Singapore. phacncg@nus.edu.sg
authors.forename: Gigi N C
authors.initials: GN
authors.lastname: Chiu
authors.forename: Lincoln A
authors.initials: LA
authors.lastname: Edwards
authors.forename: Anita I
authors.initials: AI
authors.lastname: Kapanen
authors.forename: Melina M
authors.initials: MM
authors.lastname: Malinen
authors.forename: Wieslawa H
authors.initials: WH
authors.lastname: Dragowska
authors.forename: Corinna
authors.initials: C
authors.lastname: Warburton
authors.forename: Ghania G
authors.initials: GG
authors.lastname: Chikh
authors.forename: Karen Y Y
authors.initials: KY
authors.lastname: Fang
authors.forename: Sophia
authors.initials: S
authors.lastname: Tan
authors.forename: Jonathan
authors.initials: J
authors.lastname: Sy
authors.forename: Catherine
authors.initials: C
authors.lastname: Tucker
authors.forename: Dawn N
authors.initials: DN
authors.lastname: Waterhouse
authors.forename: Richard
authors.initials: R
authors.lastname: Klasa
authors.forename: Marcel B
authors.initials: MB
authors.lastname: Bally
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D018951:Antigens, CD20 / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D002470:Cell Survival; D004268:DNA-Binding Proteins / Q000235:genetics / Q000502:physiology; D015536:Down-Regulation; D005260:Female; D005434:Flow Cytometry; D018734:Genes, erbB-2 / Q000235:genetics / Q000276:immunology; D006801:Humans; D008081:Liposomes; D051379:Mice; D018345:Mice, Knockout; D010766:Phosphorylation; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000276:immunology; D000069283:Rituximab; D015398:Signal Transduction; D051996:Transcription Factor RelA / Q000378:metabolism; D000068878:Trastuzumab
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D058846:Antibodies, Monoclonal, Murine-Derived; D000912:Antibodies, Neoplasm; D018951:Antigens, CD20; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D004268:DNA-Binding Proteins; D008081:Liposomes; D051057:Proto-Oncogene Proteins c-akt; D018719:Erb-b2 Receptor Tyrosine Kinases; D000069283:Rituximab; D051996:Transcription Factor RelA; D000068878:Trastuzumab; C499308:Rag2 protein, mouse; C498144:Rela protein, mouse