title: Novel immunocytokine IL12-SS1 (Fv) inhibits mesothelioma tumor growth in nude mice.
abstract: Mesothelin is a glycosylphosphatidylinositol-anchored glycoprotein that is highly expressed on the cell surface of malignant mesothelioma. Monoclonal antibodies against mesothelin are being evaluated for the treatment of mesothelioma. Immunocytokines represent a novel class of armed antibodies. To provide an alternative approach to current mesothelin-targeted antibody therapies, we have developed a novel immunocytokine based on interleukin-12 (IL12) and the SS1 Fv specific for mesothelin. IL12 possesses potent anti-tumor activity in a wide variety of solid tumors. The newly-developed recombinant immunocytokine, IL12-SS1 (Fv), was produced in insect cells using a baculovirus-insect cell expression system. The SS1 single-chain Fv was fused to the C terminus of the p35 subunit of IL12 through a short linker (GSADGG). The single-chain IL12-SS1 (Fv) immunocytokine bound native mesothelin proteins on malignant mesothelioma (NCI-H226) and ovarian (OVCAR-3) cells as well as recombinant mesothelin on A431/H9 cells. The immunocytokine retained sufficient bioactivity of IL12 and significantly inhibited human malignant mesothelioma (NCI-H226) grown in the peritoneal cavity of nude mice and showed comparable anti-tumor activity to that of the SS1P immunotoxin. IL12-SS1 (Fv) is the first reported immunocytokine to mesothelin-positive tumors and may be an attractive addition to mesothelin-targeted cancer therapies.
authors.affiliation: Antibody Therapy Section, Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, United States of America.
authors.forename: Heungnam
authors.initials: H
authors.lastname: Kim
authors.forename: Wei
authors.initials: W
authors.lastname: Gao
authors.forename: Mitchell
authors.initials: M
authors.lastname: Ho
mesh_terms: D000818:Animals; D000911:Antibodies, Monoclonal / Q000235:genetics*; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D005260:Female; D058851:GPI-Linked Proteins / Q000037:antagonists & inhibitors* / Q000235:genetics / Q000276:immunology; D015870:Gene Expression; D006801:Humans; D007167:Immunotherapy; D018664:Interleukin-12 / Q000235:genetics / Q000276:immunology*; D008175:Lung Neoplasms / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000090204:Mesothelin; D008654:Mesothelioma / Q000235:genetics / Q000276:immunology / Q000473:pathology / Q000628:therapy*; D000086002:Mesothelioma, Malignant; D051379:Mice; D008819:Mice, Nude; D015202:Protein Engineering; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D057127:Single-Chain Antibodies / Q000235:genetics / Q000276:immunology / Q000494:pharmacology*; D047368:Tumor Burden / Q000187:drug effects
chemical_list: D000911:Antibodies, Monoclonal; D058851:GPI-Linked Proteins; C000715528:Msln protein, mouse; D011993:Recombinant Fusion Proteins; C474515:SS1(dsFv)PE38; D057127:Single-Chain Antibodies; D018664:Interleukin-12; D000090204:Mesothelin