title: Enhancement of the antitumor properties of interleukin-2 by its targeted delivery to the tumor blood vessel extracellular matrix.
abstract: Angiogenic processes depend on the precise coordination of different cell types and a complex exchange of signals, many of which derive from new specific components of the provisional, angiogenesis-related, extracellular matrix (ECM). Angiogenesis-associated ECM components thus represent appealing targets for the selective delivery of therapeutic molecules to newly forming tumor vessels. Results of a previous study indicated that a high affinity recombinant antibody (L19) to ED-B, a domain contained in the angiogenesis-associated isoform of fibronectin (B-FN), selectively and efficiently targets tumor vessels. The present study shows that a fusion protein between L19 and interleukin 2 (L19-IL-2) mediates the selective delivery and concentration of IL-2 to tumor vasculature, thereby leading to a dramatic enhancement of the therapeutic properties of the cytokine. By contrast, IL-2 fused to an irrelevant recombinant antibody used as a control fusion protein showed neither accumulation in tumors nor therapeutic efficacy. Tumors in mice treated with L19-IL-2 were significantly smaller compared to those in animals treated with saline, the control fusion protein, or IL-2 alone (P =.003,.003, and.002, respectively). Moreover, no significant differences in size were observed among the tumors from the different control groups (using the control fusion protein, a mixture of IL-2 and L19, or saline alone). Immunohistochemical analysis of tumor infiltrates demonstrated a significantly higher number of T lymphocytes, natural killer cells, and macrophages, as well as increased interferon-gamma (IFN-gamma) accumulation, in tumors from animals treated with L19-IL-2 compared to tumors from control groups. The fact that ED-B is 100% homologous in human and mouse, thus ensuring that L19 reacts equally well with human and murine antigen, should ultimately expedite transfer of this reagent to clinical trials.
authors.affiliation: Laboratory of Cell Biology, Istituto Nazionale per la Ricerca sul Cancro, Genoa, Italy.
authors.forename: Barbara
authors.initials: B
authors.lastname: Carnemolla
authors.forename: Laura
authors.initials: L
authors.lastname: Borsi
authors.forename: Enrica
authors.initials: E
authors.lastname: Balza
authors.forename: Patrizia
authors.initials: P
authors.lastname: Castellani
authors.forename: Raffaella
authors.initials: R
authors.lastname: Meazza
authors.forename: Alexander
authors.initials: A
authors.lastname: Berndt
authors.forename: Silvano
authors.initials: S
authors.lastname: Ferrini
authors.forename: Hartwig
authors.initials: H
authors.lastname: Kosmehl
authors.forename: Dario
authors.initials: D
authors.lastname: Neri
authors.forename: Luciano
authors.initials: L
authors.lastname: Zardi
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage / Q000493:pharmacokinetics / Q000627:therapeutic use; D000951:Antigens, Neoplasm / Q000276:immunology; D000970:Antineoplastic Agents / Q000008:administration & dosage*; D001808:Blood Vessels / Q000473:pathology / Q000648:ultrastructure; D016503:Drug Delivery Systems / Q000379:methods*; D005109:Extracellular Matrix / Q000737:chemistry / Q000276:immunology; D005260:Female; D005353:Fibronectins / Q000276:immunology; D006801:Humans; D007376:Interleukin-2 / Q000008:administration & dosage* / Q000493:pharmacokinetics; D051379:Mice; D008819:Mice, Nude; D009369:Neoplasms / Q000098:blood supply / Q000188:drug therapy; D009389:Neovascularization, Pathologic / Q000188:drug therapy* / Q000473:pathology; D020033:Protein Isoforms / Q000276:immunology; D011993:Recombinant Fusion Proteins / Q000008:administration & dosage* / Q000138:chemical synthesis / Q000493:pharmacokinetics / Q000627:therapeutic use; D018243:Teratocarcinoma / Q000098:blood supply / Q000188:drug therapy; D016896:Treatment Outcome; D014407:Tumor Cells, Cultured
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; D000970:Antineoplastic Agents; D005353:Fibronectins; D007376:Interleukin-2; C554817:L19-IL2 immunocytokine; D020033:Protein Isoforms; D011993:Recombinant Fusion Proteins