The antibody-mediated targeted delivery of interleukin-15 and GM-CSF to the tumor neovasculature inhibits tumor growth and metastasis.
Tumor-targeting immunocytokines represent a new class of anticancer pharmaceutical agents, which often display a superior therapeutic index compared with the corresponding unconjugated cytokines. In this article, we have studied the anticancer properties of interleukin-15 (IL-15) and granulocyte macrophage colony-stimulating factor (GM-CSF), fused to the human antibody fragment scFv(L19), specific to the EDB domain of fibronectin, a marker of angiogenesis. The immunocytokines L19-IL-15 and L19-GM-CSF were expressed in mammalian cells and purified to homogeneity, revealing no loss of cytokine activity in in vitro assays. Furthermore, the ability of the two immunocytokines to selectively localize to tumors in vivo was confirmed by biodistribution analysis with radioiodinated protein preparations. L19-IL-15 and L19-GM-CSF displayed a potent antitumor activity both in s.c. and in metastatic F9 and C51 murine models of cancer in immunocompetent mice. This therapeutic action was superior compared with IL-15-based and GM-CSF-based fusion proteins, containing antibodies of irrelevant specificity in the mouse, which were used as non-tumor-targeting controls. For both L19-IL-15 and L19-GM-CSF immunocytokines, CD8(+) T cells seemed to mostly contribute to the therapeutic action as shown by in vivo cell depletion experiments. The results presented in this article are of clinical significance, considering the fact that the sequence of EDB is identical in mouse and man and that the tumor-targeting ability of the L19 antibody has been extensively shown in clinical trials in patients with cancer.
Kaspar
Manuela
M
Department of Chemistry and Applied Biosciences, Swiss Federal Institute of Technology, Zurich, Switzerland.
Trachsel
Eveline
E
Neri
Dario
D
D000230:Adenocarcinoma / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D000818:Animals; D048708:Cell Growth Processes / Q000187:drug effects / Q000276:immunology; D003001:Cloning, Molecular; D003110:Colonic Neoplasms / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D005260:Female; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D018796:Immunoconjugates / Q000235:genetics / Q000276:immunology / Q000493:pharmacokinetics / Q000494:pharmacology*; D007128:Immunoglobulin Fragments / Q000235:genetics / Q000276:immunology; D019409:Interleukin-15 / Q000008:administration & dosage* / Q000235:genetics / Q000493:pharmacokinetics; D051379:Mice; D008807:Mice, Inbred BALB C; D009362:Neoplasm Metastasis; D009389:Neovascularization, Pathologic / Q000276:immunology / Q000628:therapy; D013601:T-Lymphocytes / Q000276:immunology; D018243:Teratocarcinoma / Q000098:blood supply / Q000276:immunology / Q000628:therapy*; D014018:Tissue Distribution
D018796:Immunoconjugates; D007128:Immunoglobulin Fragments; D019409:Interleukin-15; D016178:Granulocyte-Macrophage Colony-Stimulating Factor