title: Enhancing the antitumor efficacy of a cell-surface death ligand by covalent membrane display.
abstract: TNF superfamily death ligands are expressed on the surface of immune cells and can trigger apoptosis in susceptible cancer cells by engaging cognate death receptors. A recombinant soluble protein comprising the ectodomain of Apo2 ligand/TNF-related apoptosis-inducing ligand (Apo2L/TRAIL) has shown remarkable preclinical anticancer activity but lacked broad efficacy in patients, possibly owing to insufficient exposure or potency. We observed that antibody cross-linking substantially enhanced cytotoxicity of soluble Apo2L/TRAIL against diverse cancer cell lines. Presentation of the ligand on glass-supported lipid bilayers enhanced its ability to drive receptor microclustering and apoptotic signaling. Furthermore, covalent surface attachment of Apo2L/TRAIL onto liposomes--synthetic lipid-bilayer nanospheres--similarly augmented activity. In vivo, liposome-displayed Apo2L/TRAIL achieved markedly better exposure and antitumor activity. Thus, covalent synthetic-membrane attachment of a cell-surface ligand enhances efficacy, increasing therapeutic potential. These findings have translational implications for liposomal approaches as well as for Apo2L/TRAIL and other clinically relevant TNF ligands.
authors.affiliation: Cancer Immunology.
authors.forename: Pradeep M
authors.initials: PM
authors.lastname: Nair
authors.affiliation: Pharmaceutical Development.
authors.forename: Heather
authors.initials: H
authors.lastname: Flores
authors.affiliation: Biomedical Imaging.
authors.forename: Alvin
authors.initials: A
authors.lastname: Gogineni
authors.affiliation: Cancer Immunology.
authors.forename: Scot
authors.initials: S
authors.lastname: Marsters
authors.affiliation: Cancer Immunology.
authors.forename: David A
authors.initials: DA
authors.lastname: Lawrence
authors.affiliation: Pharmaceutical Development.
authors.forename: Robert F
authors.initials: RF
authors.lastname: Kelley
authors.affiliation: Pathology.
authors.forename: Hai
authors.initials: H
authors.lastname: Ngu
authors.affiliation: Pathology.
authors.forename: Meredith
authors.initials: M
authors.lastname: Sagolla
authors.affiliation: Pathology.
authors.forename: Laszlo
authors.initials: L
authors.lastname: Komuves
authors.affiliation: Bioinformatics and Computational Biology, and.
authors.forename: Richard
authors.initials: R
authors.lastname: Bourgon
authors.affiliation: Discovery Oncology, Genentech, Inc., South San Francisco, CA 94080.
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Settleman
authors.affiliation: Cancer Immunology, aa@gene.com.
authors.forename: Avi
authors.initials: A
authors.lastname: Ashkenazi
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000737:chemistry*; D017209:Apoptosis; D019921:Biotinylation; D053282:CD27 Ligand / Q000378:metabolism; D053181:Caspase 8 / Q000378:metabolism; D020169:Caspases / Q000378:metabolism; D045744:Cell Line, Tumor; D002462:Cell Membrane / Q000378:metabolism*; D000939:Epitopes / Q000737:chemistry; D053222:Fas Ligand Protein / Q000378:metabolism; D006801:Humans; D007107:Immune System; D007167:Immunotherapy / Q000379:methods; D020128:Inhibitory Concentration 50; D008024:Ligands; D008081:Liposomes / Q000737:chemistry; D051379:Mice; D008819:Mice, Nude; D008856:Microscopy, Fluorescence; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000276:immunology / Q000378:metabolism; D011994:Recombinant Proteins / Q000378:metabolism; D053221:TNF-Related Apoptosis-Inducing Ligand / Q000378:metabolism*
chemical_list: D000970:Antineoplastic Agents; D053282:CD27 Ligand; D000939:Epitopes; C505661:FASLG protein, human; D053222:Fas Ligand Protein; D008024:Ligands; D008081:Liposomes; D011994:Recombinant Proteins; D053221:TNF-Related Apoptosis-Inducing Ligand; C505653:TNFSF10 protein, human; D053181:Caspase 8; D020169:Caspases
keywords: apoptosis; caspase; cell death; death receptor; membrane display