Determination of tumor-related factors of influence on the uptake of the monoclonal antibody 323/A3 in experimental human ovarian cancer

Abstract

The epithelial glycoprotein 40 (EGP40) is an important target in the clinic for radioimmunolocalization and monoclonal antibody (MAb)-mediated therapy of cancer. We determined which tumor-related factors (including antigen distribution and density, vascularization and perfusion) were involved in the uptake of the anti-EGP40 MAb 323/A3 in 4 different human ovarian cancer xenografts grown s.c. in nude mice. The reactivity pattern of 323/A3 in all xenografts in vitro was similar and showed a strong and homogeneous distribution of the EGP40 antigen. FMa xenografts, however, showed the highest uptake of 323/A3 in vivo, which was 5.5-, 6.2-and 10.0-fold higher than that in OVCAR-3, Ov.Pe and Ov.Sh xenografts, respectively. FMa xenografts contained 2.1-to 3.5-fold more antigen per gram protein when compared with the antigen content of the other xenografts. FMa and Ov.Sh xenografts demonstrated a better vascularization pattern, whereas Ov.Pe and OVCAR-3 xenografts were moderately to poorly vascularized. FMa xenografts were also better perfused, as was shown by a 1.6-to 1.8-fold higher uptake of the 99m Tc-labeled blood flow marker hexamethylpropyleneamine oxime (HMPAO). The tumor uptake of the non-specific MAb E48 was 2.2-to 11.2-fold lower when compared with that of 323/A3, but the sequence of uptake was similar (FMa G OVCAR-3 5 Ov.Pe G Ov.Sh), indicating the lowest extravasation of MAbs in Ov.Sh xenograft tissue. Since both the antigen content and the perfusion appeared to be important factors of influence on the tumor uptake of 323/A3, attempts were made to manipulate these determinants to improve the tumor uptake. Neither g-interferon nor 5-fluorouracil were able to increase EGP40 expression in human ovarian cancer cells in vitro. Treatment of tumor-bearing mice with the calcium-antagonist flunarizine did not result in an improved perfusion, although a slight increase in the initial tumor uptake of 323/A3 was observed in Ov.Sh-bearing mice. Our results illustrate the relative contribution of various tumorrelated factors that determine the usefulness of a MAb for imaging and therapy of cancer. Int.

Influence of cytokines, monoclonal antibodies and chemotherapeutic drugs on epithelial cell adhesion molecule (EpCAM) and LewisY antigen expression

“…In contrast, IFN‐ γ significantly increased only the expression of Lewis Y antigen in all three cell lines tested, which is in agreement with experiments with prostate and pancreatic cancer cell lines [24]. EpCAM was not influenced by IFN‐ γ , which is compatible with experiments with human ovarian cancer cells [25] and also prostate and pancreatic cancer cell lines [24]. A heterogeneous pattern was observed with TNF‐ α , which increased Lewis Y antigen expression only in two out of three cell lines tested.…”

Pronounced antitumor efficacy of doxorubicin when given as the prodrug DOX-GA3 in combination with a monoclonal antibody ?-glucuronidase conjugate

“…Female athymic nude mice (Hsd: athymic nude‐ nu ; Harlan, Horst, The Netherlands) were handled under specified pathogen‐free conditions. The human ovarian cancer xenograft FMa (Ep‐CAM positive) has been described earlier 20. The FMa xenograft is a poorly differentiated mucinous adenocarcinoma with a mean volume doubling time of 6.0 days.…”