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: Heungnam Kim, Wei Gao, Mitchell Ho
• Journal: PloS one (PLoS One) Vol. 8 Issue 11 Pg. e81919 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 24260587 (Publication Type: Journal Article, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• GPI-Linked Proteins
• Msln protein, mouse
• Recombinant Fusion Proteins
• SS1(dsFv)PE38
• Single-Chain Antibodies
• Interleukin-12
• Mesothelin

Topics

• Animals
• Antibodies, Monoclonal (genetics)
• Cell Line, Tumor
• Cell Survival (drug effects)
• Female
• GPI-Linked Proteins (antagonists & inhibitors, genetics, immunology)
• Gene Expression
• Humans
• Immunotherapy
• Interleukin-12 (genetics, immunology)
• Lung Neoplasms (genetics, immunology, pathology, therapy)
• Mesothelin
• Mesothelioma (genetics, immunology, pathology, therapy)
• Mesothelioma, Malignant
• Mice
• Mice, Nude
• Protein Engineering
• Recombinant Fusion Proteins (genetics, immunology, pharmacology)
• Single-Chain Antibodies (genetics, immunology, pharmacology)
• Tumor Burden (drug effects)