title: The antibody-mediated targeted delivery of interleukin-13 to syngeneic murine tumors mediates a potent anticancer activity.
abstract: We describe the expression and in vivo characterization of an antibody-cytokine fusion protein, based on murine Interleukin-13 (IL13) and the monoclonal antibody F8, specific to the alternatively spliced extra domain A of fibronectin, a marker of neo-angiogenesis. The IL13 moiety was fused at the C-terminal extremity of the F8 antibody in diabody format. The resulting F8-IL13 immunocytokine retained the full binding properties of the parental antibody and cytokine bioactivity. The fusion protein could be expressed in mammalian cells, purified to homogeneity and showed a preferential accumulation at the tumor site. When used as single agent at doses of 200 μg, F8-IL13 exhibited a strong inhibition of tumor growth rate in two models of cancer (F9 teratocarcinoma and Wehi-164), promoting an infiltration of various types of leukocytes into the neoplastic mass. This anticancer activity could be potentiated by combination with an immunocytokine based on the F8 antibody and murine IL12, leading to complete and long-lasting tumor eradications. Mice cured from Wehi-164 sarcomas acquired a durable protective antitumor immunity, and selective depletion of immune cells revealed that the antitumor activity was mainly mediated by cluster of differentiation 4-positive T cells. This study indicates that IL13 can be efficiently delivered to the tumor neo-vasculature and that it mediates a potent anticancer activity in the two models of cancer investigated in this study. The observed mechanism of action for F8-IL13 was surprising, since immunocytokines based on other payloads (e.g., IL2, IL4, IL12 and TNF) eradicate cancer by the combined contribution of natural killer cells and cluster of differentiation 8-positive T cells.
authors.affiliation: Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology Zurich (ETH Zürich), Vladimir-Prelog-Weg 1-5/10, 8093, Zurich, Switzerland.
authors.forename: Christian
authors.initials: C
authors.lastname: Hess
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage* / Q000235:genetics; D061067:Antibodies, Monoclonal, Humanized; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D016466:CHO Cells; D002460:Cell Line; D003412:Cricetulus; D016503:Drug Delivery Systems; D005260:Female; D005354:Fibrosarcoma / Q000188:drug therapy* / Q000276:immunology; D018793:Interleukin-13 / Q000008:administration & dosage* / Q000235:genetics; D008213:Lymphocyte Activation / Q000187:drug effects / Q000276:immunology; D008212:Lymphocyte Depletion; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000096:biosynthesis / Q000235:genetics; D018243:Teratocarcinoma / Q000188:drug therapy* / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; C528643:F8 monoclonal antibody; D018793:Interleukin-13; D011993:Recombinant Fusion Proteins