Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12

Roberto Sommavilla, Nadine Pasche, Eveline Trachsel, Leonardo Giovannoni, Christoph Roesli, Alessandra Villa, Dario Neri, Manuela Kaspar

Research output: Contribution to journalArticle

Abstract

Proinflammatory cytokines have been used for several years in patients with advanced cancer but their administration is typically associated with severe toxicity hampering their application to therapeutically active regimens. This problem can be overcome by using immunocytokines (cytokines fused to antibody or antibody fragments) which selectively deliver the active cytokine to the tumor environment. Preclinical and recent clinical results confirmed that this approach is a very promising avenue to go. We designed an immunocytokine consisting of the scFv(F8) specific to extra-domain A of fibronectin and the very potent human cytokine interleukin-12 (IL12). The heterodimeric nature of IL12 allows the engineering of various immunocytokine formats, based on different combinations of the two subunits (p35 and p40) together with the scFv. In comparison to monomeric or homodimeric cytokines, the construction of a heterodimeric immunocytokine poses many challenges, e.g. gene dosing, stable high-yield expression as well as good manufacture practice (GMP) purification and characterization. In this paper, we describe the successful construction, characterization and production of the heterodimeric immunocytokine F8-IL12. The positive outcome of this feasibility study leads now to GMP production of F8-IL12, which will soon enter clinical trials.

Original languageEnglish
Pages (from-to)653-661
Number of pages9
JournalProtein Engineering, Design and Selection
Volume23
Issue number8
DOIs
Publication statusPublished - 2010

Keywords

  • heterodimer
  • immunocytokine
  • interleukin 12
  • scFv antibody fragment

ASJC Scopus subject areas

  • Biochemistry
  • Biotechnology
  • Bioengineering
  • Molecular Biology
  • Medicine(all)

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    Sommavilla, R., Pasche, N., Trachsel, E., Giovannoni, L., Roesli, C., Villa, A., Neri, D., & Kaspar, M. (2010). Expression, engineering and characterization of the tumor-targeting heterodimeric immunocytokine F8-IL12. Protein Engineering, Design and Selection, 23(8), 653-661. https://doi.org/10.1093/protein/gzq038