title: Tumor pretargeting with avidin improves the therapeutic index of biotinylated tumor necrosis factor alpha in mouse models.
abstract: The clinical use of tumor necrosis factor alpha (TNF) as an anticancer drug is limited to local or locoregional administration because of dose-limiting systemic toxicity. We investigated in animal models whether the therapeutic index of systemically administered human or murine TNF can be increased by tumor pretargeting strategies based on the biotin-avidin system. Pretargeting of s.c. mouse WEHI-164 fibrosarcoma and RMA lymphoma genetically engineered to express the Thy 1.1 antigen on the cell membrane was achieved by i.p. injection of a biotinylated anti-Thy 1.1 antibody and avidin. This pretreatment increased the antitumor activity of systemically administered biotin-TNF conjugates by at least 5-fold. In contrast, pretargeting did not increase the toxicity of biotin-TNF, as judged by animal survival and weight loss after treatment. Ex vivo analysis of tumor cells 24 h after treatment showed that biotin-TNF persisted for several hours on the surface of pretargeted tumors, but not when avidin was omitted. The potentiation of the antitumor effects was related primarily to indirect mechanisms, involving a host-mediated response. The results indicate that tumor pretargeting improves the antitumor activity of TNF. Tumor pretargeting with avidin, which is currently used to increase the uptake of radioactive-labeled biotin in patients, could represent a new strategy for improving the therapeutic index of TNF.
authors.affiliation: Department of Biological and Technological Research, San Raffaele H Scientific Institute, Milan, Italy.
authors.forename: A
authors.initials: A
authors.lastname: Gasparri
authors.forename: M
authors.initials: M
authors.lastname: Moro
authors.forename: F
authors.initials: F
authors.lastname: Curnis
authors.forename: A
authors.initials: A
authors.lastname: Sacchi
authors.forename: S
authors.initials: S
authors.lastname: Pagano
authors.forename: F
authors.initials: F
authors.lastname: Veglia
authors.forename: G
authors.initials: G
authors.lastname: Casorati
authors.forename: A G
authors.initials: AG
authors.lastname: Siccardi
authors.forename: P
authors.initials: P
authors.lastname: Dellabona
authors.forename: A
authors.initials: A
authors.lastname: Corti
mesh_terms: D000818:Animals; D000970:Antineoplastic Agents / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity; D001360:Avidin / Q000627:therapeutic use*; D019921:Biotinylation; D016503:Drug Delivery Systems; D006801:Humans; D008223:Lymphoma / Q000188:drug therapy*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D011994:Recombinant Proteins / Q000378:metabolism / Q000627:therapeutic use / Q000633:toxicity; D012513:Sarcoma, Experimental / Q000188:drug therapy*; D014407:Tumor Cells, Cultured; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism / Q000627:therapeutic use* / Q000633:toxicity
chemical_list: D000970:Antineoplastic Agents; D011994:Recombinant Proteins; D014409:Tumor Necrosis Factor-alpha; D001360:Avidin