Preclinical evaluation of a recombinant anti-prostate specific membrane antigen single-chain immunotoxin against prostate cancer

Philipp Wolf, Karen Alt, David Wetterauer, Patrick Bühler, Dorothee Gierschner, Arndt Katzenwadel, Ulrich Wetterauer, Ursula Elsässer-Beile

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29 Citations (Scopus)

Abstract

The prostate-specific membrane antigen (PSMA) is abundantly expressed on prostate cancer epithelial cells and its expression correlates with tumor progression. Therefore, a specific immunotherapy against this antigen may be a novel therapeutic option for the management of prostate cancer. We generated an anti-PSMA singlechain antibody fragment (scFv), called D7, by phage display from the monoclonal antibody 3/F11. By C-terminal ligation of the toxic domain of Pseudomonas Exotoxin A (PE40) to the genes of D7, the immunotoxin D7-PE40 was generated. D7 and D7-PE40 specifically bound to PSMA transfectants and to the PSMA expressing prostate cancer cell line C4-2. In addition, D7-PE40 showed a high serum stability and induced a 50% reduction of viability (IC 50) in C4-2 cells at a concentration of 140 pM. In vivo, D7-PE40 was well tolerated in SCID mice up to a single dose of 20 μg, whereas higher doses induced severe hepatotoxicity with deaths of the animals. Immunotoxin treatment of mice bearing C4-2 tumor xenografts caused a significant inhibition of tumor growth, whereas mice with PSMA-negative DU 145 tumors remained unaffected. Owing to its high and specific cytotoxicity and its capability to inhibit prostate tumor growth in vivo the immunotoxin D7-PE40 represents a promising candidate for the immunotherapy of prostate cancer.

Original languageEnglish
Pages (from-to)262-271
Number of pages10
JournalJournal of immunotherapy (Hagerstown, Md. : 1997)
Volume33
Issue number3
DOIs
Publication statusPublished - Apr 2010
Externally publishedYes

Keywords

  • Immunotherapy
  • Immunotoxin
  • Prostate cancer
  • Pseudomonas Exotoxin A
  • PSMA

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