Anti-tumor effects of toxins targeted to the prostate specific membrane antigen.
BACKGROUND
There is presently no effective therapy for relapsing, metastatic, androgen-independent prostate cancer. Immunotherapy with monoclonal antibody-vehicled toxins (Immunotoxins, ITs) may be a promising novel treatment option for the management of prostate cancer in these cases.


METHODS
Three anti-prostate specific membrane antigen (anti-PSMA) monoclonals (J591, PEQ226.5, and PM2P079.1) were cross-linked to ricin A-chain (RTA; native or recombinant), and their cytotoxic effects were investigated in monolayer and three-dimensional (3-D) cell cultures of prostate carcinoma cells (LNCaP).


RESULTS
The various Immunotoxins showed effects in the nanomolar range (IC(50s) of 1.6-99 ng/ml) against PSMA+ cells (IC(50) being the concentration inhibiting 50% cell proliferation or protein synthesis). PSMA(-) cell lines were 62- to 277-fold less sensitive to anti-PSMA ITs, evidencing an appreciable therapeutic window. Treatment with J591-smpt-nRTA (0.35-31.7ng/ml) resulted in complete eradication of 3-D tumor micromasses or in 1.46- to 0.35-log reduction of target cells number, depending on the dose.


CONCLUSIONS
Anti-PSMA ITs appear to be promising for use in the eradication of small prostate tumor cell aggregates present in tissues and in the bone marrow.
Fracasso
Giulio
G
Section of Immunology, Department of Pathology, University of Verona, Verona, Italy.
Bellisola
Giuseppe
G
Cingarlini
Sara
S
Castelletti
Deborah
D
Prayer-Galetti
Tommaso
T
Pagano
Francesco
F
Tridente
Giuseppe
G
Colombatti
Marco
M
D000911:Antibodies, Monoclonal / Q000627:therapeutic use; D000954:Antigens, Surface; D001859:Bone Neoplasms / Q000556:secondary; D002268:Carboxypeptidases / Q000276:immunology / Q000494:pharmacology*; D002277:Carcinoma / Q000473:pathology*; D043425:Glutamate Carboxypeptidase II; D006801:Humans; D000922:Immunotoxins / Q000276:immunology / Q000494:pharmacology*; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D012276:Ricin / Q000008:administration & dosage / Q000494:pharmacology*; D014407:Tumor Cells, Cultured
D000911:Antibodies, Monoclonal; D000954:Antigens, Surface; D000922:Immunotoxins; D012276:Ricin; D002268:Carboxypeptidases; C473848:FOLH1 protein, human; D043425:Glutamate Carboxypeptidase II