Targeting of the Tn antigen by a specific chimeric monoclonal antibody in ovarian cancer immunotherapy – ANTITN

Therapeutic monoclonal antibodies (mAb) specific for tumor-cell surface antigens are efficient at eradicating patients’ cancers. These enthousiastic results encourage us to develop new tumor-specific mAbs, mainly against cancers with bad prognosis like ovarian cancer. Tn is a glyco-peptidic antigen (GalNac-O-Ser/Threo) which is expressed in human carcinomas because of dysregulations of glycosylation processes. The great advantage of the Tn antigen is to discriminates tumor cells from their healthy counterpart with high selectivity. Tn is strongly expressed in 90% of ovarian cancers, and is thus a good candidate for antibody-mediated cancer immunotherapy.
In a preliminary study, we showed that a chimeric mAb specific for the Tn antigen (Chi-Tn mAb) inhibited tumor growth when associated with cyclophosphamide (CTX) in a syngenic mouse tumor model. Chi-Tn was not directly toxic for tumor cells, but induced tumor cell death by ADCC. Moreover, we showed that the Chi-Tn mAb was internalized into tumor cells and that the Chi-Tn mAb conjugated to the toxin saporin killed tumor cells in vitro.
The aim of this project is to reinforce the proof of concept of the efficiency of this Chi-Tn mAb in xenograft models of ovarian cancer, which is a necessary step before starting a clinical development phase. We will use two therapeutic approaches using the Chi-Tn mAb as an anti-cancer agent. The first one will use an uncoupled form of the Chi-Tn mAb to destroy Tn-positive tumor cells by ADCC. The second approach will use the Chi-Tn mAb as a vector to target cytotoxic drugs to the tumor.
We will use two kinds of xenograft models of ovarian tumors in Nude mice. Cell line xenografts will be obtained by grafting Tn+ human ovarian tumor cell lines. For primary tumor xenografts models, Nude mice will receive a subcutaneous graft of Tn+ tumor fragments obtained from ovarian cancer patients. These models are already available in the Institut Curie.
The anti-tumor effect of the uncoupled Chi-Tn mAb in association with CTX will be first tested in cell line xenograft models, then in primary xenograft models. In addition, we will seek for a synergistic anti-tumor effect between Chi-Tn and the chemotherapeutic drugs used in ovarian cancer therapy - carboplatin and paclitaxel - in order to find other treatment combinations for patients.
The Chi-Tn mAb conjugated to the toxin saporin (Chi-Tn-Sap) will be used to make the proof of concept of the efficacy of Chi-Tn as a targeting vector for cytotoxic drugs towards the tumors. The anti-tumor effect of Chi-Tn-Sap will be first studied in vitro on the ovarian tumor cell lines used for the xenograft models and on fresh tumor cells from ovarian cancer patients’ ascitis. After assessment of the Chi-Tn-Sap mAb maximal tolerated dose in mice, its anti-tumor effect will be determined in vivo in cell line xenograft models and in primary xenograft models.
The end point of this project is to find at least one therapeutic combination where the Chi-Tn mAb has a statistically significant anti-tumor effect in one of the models. These results will be critical to decide the launching of the clinical development phases of the uncoupled Chi-Tn mAb and/or of the Chi-Tn mAb conjugated to a cytotoxic drug. This development phase will be performed in collaboration with a private pharmaceutical company. This project will help bring new therapeutic tools for ovarian cancer therapy.