In vitro activity of immunoconjugates between cisplatin and an anti-CA125 monoclonal antibody on ovarian cancer cell lines

Abstract

Cis-diammine dichloro platinum (II) (CDDP), is a highly potent antineoplastic agent that is used in the treatment of ovarian cancer. However, the clinical use of CDDP is restricted by its severe side effects. In order to reduce these side effects and to enhance its therapeutic efficacy, we developed specific immunoconjugates consisting of the murine monoclonal antibody OC125 and CDDP, using diethylene triamine pentaacetic acid (DTPA) as a linker. The coupling efficiencies of the different preparations synthesized, varied between 1.10 +/- 0.42 and 2.65 +/- 1.60 mol of CDDP per mol of antibody protein. Despite the chemical modification of the antibody molecule, specific binding activity of the OC125-CDDP conjugates toward the CA125 antigen was maintained as was demonstrated by means of immunohisto-/cytochemical staining of frozen sections of ovarian cancer tissue, amniotic epithelium, and the CA125 positive ovarian cancer cell line NIH:OVCAR 3. The antiproliferative activity of the immunoconjugates was tested against the human ovarian cancer cell lines NIH:OVCAR 3 and SKOV 3, applying a kinetic crystal violet microassay. Despite the promising results obtained with the specific immunostaining of the target cells, no significant antiproliferative activity of our immunoconjugates against the cell lines tested was observed. One possible explanation for the lack of antitumor activity could be the fact that CA125 is released in large amounts by the NIH:OVCAR 3 cells. This may have prevented an efficient immunotargeting of the cancer cells by the formation of soluble immune complexes.

Biodistribution of charged F(ab')2 photoimmunoconjugates in a xenograft model of ovarian cancer

“…OC125 is a murine monoclonal antibody that recognizes the cell-surface antigen CA 125, a 1000-kDa glycoprotein (Hosono et al, 1992) expressed by 85% of non-mucinous epithelial ovarian cancers (Karlan et al, 1988). Conjugates of OC125 with radioisotopes (Haisma et al, 1988;Muto et al, 1992) and cytotoxic drugs (Beck et al, 1994) have been administered i.p. to target ovarian cancer in both animals and humans.…”

Immunologische und innovative Therapieformen beim Ovarialkarzinom

“…Der Vergleich mit dem Einfluß der Zytostatika ohne das Targeting zeigte eine signifikant bessere Wirkung der Konjugate. Versuche an den Zellinien OVCAR 3 und SKOV 3 mit einem Konjugat aus Anti-CA 125 und Cisplatin erbrachte enttäu-schende Ergebnisse, die im einzelnen noch ungeklärt sind [9]. Möglicher-weise verhindern spezifische Eigenschaften der Zellinien eine entsprechende Wirkung; so soll die Zellinie SKOVK 3 erhebliche Mengen an CA 125 produzieren und abschilfern mit der Folge, daß fern der Zellen Komplexe zwischen den Antikörpern und dem freigesetzten CA 125 eine frühzeitige Bindung und Verbrauch des Immunkonjugats bewirken.…”