Anti-PSMA immunotoxin as novel treatment for prostate cancer? High and specific antitumor activity on human prostate xenograft tumors in SCID mice.
BACKGROUND
Expression of the prostate specific membrane antigen (PSMA) is highly restricted to prostate epithelial cells. Therefore, toxin-based immunotherapy against this antigen may represent an alternative therapeutic option for prostate cancer. For these purposes, the effects of the recombinant anti-PSMA immunotoxin A5-PE40 on prostate tumor growth were investigated in vitro and in vivo.


METHODS
The in vitro binding and cytotoxicity of A5-PE40 were tested on the PSMA-expressing prostate cancer cell line C4-2 and on the PSMA-negative cell line DU145 by flow cytometry and WST assays. The binding of the immunotoxin to SCID mouse xenografts and to various mouse organs was examined by Western blot analysis. In vivo, the antitumor activity of the immunotoxin was tested by injecting A5-PE40 in mice bearing C4-2 or DU145 xenografts.


RESULTS
In vitro, a specific binding of A5-PE40 to C4-2 cells could be shown with a concentration-dependent cytotoxicity (IC(50) value=220 pM). In the next step, a specific binding of the immunotoxin to C4-2 xenografts could be demonstrated. In contrast, no binding on mouse organs expressing high homologous mouse PSMA was found. The treatment of mice with C4-2 tumors caused a significant inhibition of tumor growth in vivo, whereas DU145 xenografts remained totally unaffected.


CONCLUSIONS
A5-PE40 represents a recombinant anti-PSMA immunotoxin with potent antitumor activity in mice bearing human prostate cancer xenograft tumors. Therefore, A5-PE40 could be a promising candidate for therapeutic applications in patients with prostate cancer.
Department of Urology, Experimental Urology, University of Freiburg, Freiburg, Germany.
Philipp
P
Wolf
Karen
K
Alt
Patrick
P
Bühler
Arndt
A
Katzenwadel
Ulrich
U
Wetterauer
Marlene
M
Tacke
Ursula
U
Elsässer-Beile
D036002:ADP Ribose Transferases / Q000276:immunology / Q000627:therapeutic use*; D000818:Animals; D000918:Antibody Specificity / Q000276:immunology; D000970:Antineoplastic Agents / Q000276:immunology / Q000627:therapeutic use*; D001427:Bacterial Toxins / Q000276:immunology / Q000627:therapeutic use*; D045744:Cell Line, Tumor; D004361:Drug Tolerance; D005098:Exotoxins / Q000276:immunology / Q000627:therapeutic use*; D006801:Humans; D007167:Immunotherapy / Q000379:methods; D000922:Immunotoxins / Q000276:immunology / Q000627:therapeutic use*; D008297:Male; D051379:Mice; D016513:Mice, SCID; D017430:Prostate-Specific Antigen / Q000276:immunology*; D011471:Prostatic Neoplasms / Q000188:drug therapy* / Q000473:pathology; D037521:Virulence Factors / Q000276:immunology / Q000627:therapeutic use*; D023041:Xenograft Model Antitumor Assays / Q000379:methods*; D000097668:Pseudomonas aeruginosa Exotoxin A
D036002:ADP Ribose Transferases; D000970:Antineoplastic Agents; D001427:Bacterial Toxins; D005098:Exotoxins; D000922:Immunotoxins; D017430:Prostate-Specific Antigen; D037521:Virulence Factors; D000097668:Pseudomonas aeruginosa Exotoxin A