title: The immunocytokine NHS-IL12 as a potential cancer therapeutic.
abstract: Targeted delivery of IL-12 might turn this cytokine into a safer, more effective cancer therapeutic. Here we describe a novel immunocytokine, NHS-IL12, consisting of two molecules of IL-12 fused to a tumor necrosis-targeting human IgG1 (NHS76). The addition of the human IgG1 moiety resulted in a longer plasma half-life of NHS-IL12 than recombinant IL-12, and a selective targeting to murine tumors in vivo. Data from both in vitro assays using human PBMCs and in vivo primate studies showed that IFN-gamma production by immune cells is attenuated following treatment with the immunocytokine, suggesting an improved toxicity profile than seen with recombinant IL-12 alone. NHS-IL12 was superior to recombinant IL-12 when evaluated as an anti-tumor agent in three murine tumor models. Mechanistic studies utilizing immune cell subset-depleting antibodies, flow cytometric methods, and in vitro cytotoxicity and ELISA assays all indicated that the anti-tumor effects of NHS-IL12 were primarily CD8+ T cell-dependent and likely IL-12-mediated. Combining NHS-IL12 treatment with a cancer vaccine, radiation, or chemotherapy resulted in greater anti-tumor effects than each individual therapy alone. These preclinical findings provide a rationale for the clinical testing of this immunocytokine, both as a single agent and in combination with vaccines, radiation and chemotherapy.
authors.affiliation: Laboratory of Tumor Immunology and Biology, Center for Cancer Research, National Cancer Institute, Bethesda, Maryland USA;
authors.forename: Jonathan
authors.initials: J
authors.lastname: Fallon
authors.forename: Robert
authors.initials: R
authors.lastname: Tighe
authors.forename: Giorgio
authors.initials: G
authors.lastname: Kradjian
authors.forename: Wilson
authors.initials: W
authors.lastname: Guzman
authors.forename: Anna
authors.initials: A
authors.lastname: Bernhardt
authors.forename: Berend
authors.initials: B
authors.lastname: Neuteboom
authors.forename: Yan
authors.initials: Y
authors.lastname: Lan
authors.forename: Helen
authors.initials: H
authors.lastname: Sabzevari
authors.forename: Jeffrey
authors.initials: J
authors.lastname: Schlom
authors.forename: John W
authors.initials: JW
authors.lastname: Greiner
mesh_terms: D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D018414:CD8-Positive T-Lymphocytes; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000627:therapeutic use; D045744:Cell Line, Tumor; D000077143:Docetaxel; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D056747:Immunomodulation; D007211:Indoles / Q000008:administration & dosage; D007371:Interferon-gamma / Q000378:metabolism*; D018664:Interleukin-12 / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D008213:Lymphocyte Activation / Q000187:drug effects; D008252:Macaca fascicularis; D008562:Membrane Glycoproteins / Q000627:therapeutic use; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D009374:Neoplasms, Experimental / Q000628:therapy*; D015202:Protein Engineering; D011758:Pyrroles / Q000008:administration & dosage; D011993:Recombinant Fusion Proteins / Q000276:immunology / Q000494:pharmacology* / Q000627:therapeutic use; D000077210:Sunitinib; D015996:Survival Rate; D043823:Taxoids / Q000008:administration & dosage; D047368:Tumor Burden
chemical_list: D019496:Cancer Vaccines; D007074:Immunoglobulin G; D007211:Indoles; C518273:L-BLP25; D008562:Membrane Glycoproteins; C000594734:NHS-IL12 immunocytokine; D011758:Pyrroles; D011993:Recombinant Fusion Proteins; D043823:Taxoids; D000077143:Docetaxel; D018664:Interleukin-12; D007371:Interferon-gamma; D000077210:Sunitinib