An engineered antibody-interleukin-12 fusion protein with enhanced tumor vascular targeting properties.
The antibody-mediated targeted delivery of interleukin-12 (IL12) to the EDB domain of fibronectin, a marker of angiogenesis, is a promising avenue for enhancing the therapeutic index of this anti-cancer cytokine. Previous experiments, based on sequential fusion of a single-chain IL12 derivative to the anti-EDB antibody fragment scFv(L19) had yielded a therapeutic fusion protein [IL12-scFv(L19)-FLAG], which displayed an impressive therapeutic activity in murine models of cancer, in spite of a tumor uptake, which was less efficient compared to the parental unmodified scFv(L19). In this article, we describe the comparative analysis of 3 recombinant fusion proteins comprising the scFv(L19) and IL12 moieties. One of them, in which the p40 and p35 form a covalent heterodimer and in which each subunit is fused to a molecule of scFv(L19), displays an excellent tumor targeting performance in vivo, as assessed by quantitative biodistribution analysis, and a potent anti-tumor effect, superior to the one of IL12-scFv(L19)-FLAG. These results may have a clinical impact, considering the fact that the tumor targeting ability of scFv(L19) in patients with cancer has been demonstrated using scintigraphic methods, and that 2 scFv(L19)-based antibody-cytokine fusion are currently entering clinical trials.
Gafner
Verena
V
Institute of Pharmaceutical Sciences, Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zürich, Switzerland.
Trachsel
Eveline
E
Neri
Dario
D
D020533:Angiogenesis Inhibitors / Q000627:therapeutic use; D000818:Animals; D002460:Cell Line; D045744:Cell Line, Tumor; D006801:Humans; D018664:Interleukin-12 / Q000235:genetics / Q000627:therapeutic use*; D007668:Kidney; D051379:Mice; D009369:Neoplasms / Q000098:blood supply*; D009389:Neovascularization, Pathologic / Q000517:prevention & control*; D015202:Protein Engineering / Q000379:methods; D011993:Recombinant Fusion Proteins / Q000627:therapeutic use*
D020533:Angiogenesis Inhibitors; D011993:Recombinant Fusion Proteins; D018664:Interleukin-12