Targeted therapy against human lung cancer in nude mice by high-affinity recombinant antimesothelin single-chain Fv immunotoxin.

Abstract

Several tumors, including mesothelioma and ovarian cancer, can overexpress mesothelin, a glycosylphosphatidylinositol-linked differentiation glycoprotein. The membrane-bound type of mesothelin is found in the blood of cancer patients at a very low level, which makes mesothelin a good candidate for targeted therapy of certain cancers. An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM). Our studies in vitro showed that SS1(dsFv)-PE38 is significantly more cytotoxic to the high-mesothelin-producing NCI-H226 human non-small cell lung cancer cells than to human lung adenocarcinoma PC14PE6 cells, which do not express mesothelin. When administered at a nontoxic dose of 500 microg/kg on days 7, 9, and 11 to nude mice injected i.v. with the two human lung cancer cell lines, SS1(dsFv)-PE38 selectively inhibited experimental lung metastases produced by the mesothelin-producing NCI-H226 cells. Our data indicate that mesothelin-producing squamous cell carcinoma of the lung may be a good target for this immunotoxin.

• Authors: Dominic Fan, Seiji Yano, Hisashi Shinohara, Carmen Solorzano, Melissa Van Arsdall, Corazon D Bucana, Sen Pathak, Ewa Kruzel, Roy S Herbst, Amir Onn, Jennifer S Roach, Masanori Onda, Qing-cheng Wang, Ira Pastan, Isaiah J Fidler
• Journal: Molecular cancer therapeutics (Mol Cancer Ther) Vol. 1 Issue 8 Pg. 595-600 (Jun 2002) ISSN: 1535-7163 [Print] United States
• PMID: 12479219 (Publication Type: Journal Article, Research Support, U.S. Gov't, P.H.S.)

Chemical References

• Bacterial Toxins
• Exotoxins
• Immunoglobulin Fragments
• Msln protein, mouse
• Recombinant Proteins
• Virulence Factors
• immunoglobulin Fv
• ADP Ribose Transferases
• Mesothelin

Topics

• ADP Ribose Transferases (metabolism)
• Animals
• Bacterial Toxins (metabolism)
• Dose-Response Relationship, Drug
• Exotoxins (metabolism)
• Flow Cytometry
• Humans
• Immunoglobulin Fragments (therapeutic use)
• Immunotherapy (methods)
• Kinetics
• Lung Neoplasms (therapy)
• Mesothelin
• Mice
• Mice, Nude
• Microscopy, Fluorescence
• Mutation
• Neoplasm Transplantation
• Pseudomonas (metabolism)
• Recombinant Proteins (pharmacology)
• Tumor Cells, Cultured
• Virulence Factors (metabolism)
• Pseudomonas aeruginosa Exotoxin A