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A novel anti-cancer L19-interleukin-12 fusion protein with an optimized peptide linker efficiently localizes in vivo at the site of tumors.

Abstract
Antibody-cytokine fusion proteins are a class of biopharmaceuticals, with the potential to modulate the activity of the immune system at the site of disease. The molecular format used to connect antibody moiety and cytokine payload can have a profound influence on biological activity and pharmacokinetic properties. The optimization of fusion protein format is particularly challenging for heterodimeric cytokines, since various molecular arrangements can be considered. In this article, we have explored the role of linker in a tumor-targeting IL12 fusion protein, based on the L19 antibody, specific to the extra-domain B of fibronectin. In biodistribution studies performed in tumor-bearing mice using radioiodinated protein preparations, fusion of human IL12 at the N-terminus of the L19 antibody in tandem-diabody format led to higher tumor uptake and improved tumor-to-organ ratios, compared to a similar fusion protein featuring L19 in IgG1 format. Moreover, optimization of the amino acid composition in eight variants of the linker connecting the IL12 moiety to the tandem-diabody revealed that a 15-amino acid linker (GSADGGSSAGGSDAG) displayed the best tumor targeting characteristics, with a long residence time at the tumor site and a rapid clearance from blood and normal organs. The product is being developed for industrial and clinical applications.
AuthorsTiziano Ongaro, Mattia Matasci, Samuele Cazzamalli, Baptiste Gouyou, Roberto De Luca, Dario Neri, Alessandra Villa
JournalJournal of biotechnology (J Biotechnol) Vol. 291 Pg. 17-25 (Feb 10 2019) ISSN: 1873-4863 [Electronic] Netherlands
PMID30586544 (Publication Type: Journal Article)
CopyrightCopyright © 2018 Elsevier B.V. All rights reserved.
Chemical References
  • Antibodies
  • Antineoplastic Agents, Immunological
  • Peptides
  • Recombinant Fusion Proteins
  • Interleukin-12
Topics
  • Animals
  • Antibodies (genetics, therapeutic use)
  • Antineoplastic Agents, Immunological (therapeutic use)
  • CHO Cells
  • Cell Line, Tumor
  • Cricetulus
  • Female
  • Interleukin-12 (genetics, therapeutic use)
  • Mice
  • Neoplasms (drug therapy)
  • Peptides (genetics, therapeutic use)
  • Recombinant Fusion Proteins (therapeutic use)

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