Tumor pretargeting with avidin improves the therapeutic index of biotinylated tumor necrosis factor α in mouse models

Anna Gasparri, Monica Moro, Flavio Curnis, Angelina Sacchi, Stefano Pagano, Fabrizio Veglia, Giulia Casorati, Antonio G. Siccardi, Paolo Dellabona, Angelo Corti

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Abstract

The clinical use of tumor necrosis factor α (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.

Original languageEnglish
Pages (from-to)2917-2923
Number of pages7
JournalCancer Research
Volume59
Issue number12
Publication statusPublished - Jun 15 1999

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Avidin
Tumor Necrosis Factor-alpha
Biotin
Neoplasms
Therapeutics
Thy-1 Antigens
Fibrosarcoma
Weight Loss
Lymphoma
Animal Models
Cell Membrane
Injections
Pharmaceutical Preparations

ASJC Scopus subject areas

  • Cancer Research
  • Oncology

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Tumor pretargeting with avidin improves the therapeutic index of biotinylated tumor necrosis factor α in mouse models. / Gasparri, Anna; Moro, Monica; Curnis, Flavio; Sacchi, Angelina; Pagano, Stefano; Veglia, Fabrizio; Casorati, Giulia; Siccardi, Antonio G.; Dellabona, Paolo; Corti, Angelo.

In: Cancer Research, Vol. 59, No. 12, 15.06.1999, p. 2917-2923.

Research output: Contribution to journalArticle

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AU - Veglia, Fabrizio

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