Two of the four cell lines available to this study, one uterine and one ovarian, were found have elevatedTrop-2 expression, with one cell line (OMMT-ARK-2) expressing high Trop-2 VX809 mRNA relative expression by PCR as well as high surface level Trop-2 protein expression by flow cytometry. This highly expressing cell line was found to have corresponding high sensitivity to hRS7-mediated ADCC, while negligible killing was detected in the presence of allogeneic PBL in the absence of hRS7 or in the presence of rituximab, used as a control antibody. These results suggest that uterine and ovarian carcinosarcomas, which are notoriously resistant to multiple

clinically available

chemotherapeutic agents [5, 6], can be made highly sensitive to immune-mediated cytotoxicity when effector cells are engaged by the Trop-2-specific antibody, hRS7. In vivo, ADCC applications are known to be dependent upon the availability of the effector cells (mainly natural killer cells) to interact with the antibody at the target site in the presence of high concentrations of irrelevant human IgG. In this study, we show that ADCC against carcinosarcomas Selleckchem Verteporfin was not significantly inhibited by high concentrations (up to 50%) of human plasma. In fact, a consistent increase in cytotoxicity was detected in the presence of effector cells and non-heat-inactivated human plasma. This suggests that in the presence of effector PBL, human plasma may augment hRS7-mediated cytotoxicity against carcinosarcomas. Moreover, these results indicate that the binding of hRS7 to the Fc receptor on mononuclear effector cells is likely to occur in the in vivo setting. Conclusions In conclusion, this is the first report on Trop-2

protein expression and hRS7 antibody-dependent cellular cytotoxicity in uterine and ovarian carcinosarcomas. We report Trop-2 overexpression in 35% of uterine and 57% of the ovarian BIBF 1120 concentration carcinosarcoma tested by IHC and in two out of four primary carcinosarcoma cell lines available C-X-C chemokine receptor type 7 (CXCR-7) to this study, and we have provided evidence that increased surface expression of Trop-2 is associated with increased cancer cell susceptibility to immune-mediated cytotoxicity in the presence of hRS7. Although in vivo data will ultimately be necessary to validate the therapeutic potential of hRS7 against Trop-2-expressing carcinosarcomas, our in vitro results suggest that targeting cancer cells with high surface expression of Trop-2 may be an effective way to treat residual or resistant uterine and ovarian carcinosarcomas. Acknowledgements The authors thank Immunomedics, Inc., (Morris Plains, NJ), for providing hRS7 monoclonal antibody without charge for our studies.