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

Mol Cancer Ther. 2002 Jun;1(8):595-600.

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.

Publication types

  • Research Support, U.S. Gov't, P.H.S.

MeSH terms

  • 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
  • Pseudomonas aeruginosa Exotoxin A
  • Recombinant Proteins / pharmacology*
  • Tumor Cells, Cultured
  • Virulence Factors / metabolism

Substances

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