Novel Targets And Monoclonal Antibodies For Cancer Therapy

The identification of markers targetable by specific mAbs represents a high medical need in cancer therapy. Our objective is to discover novel tumor-associated proteins showing promise as targets for monoclonal antibody (mAb) therapy, and to generate and validate highly specific mAbs for therapeutic applications. The approach we used to discover novel tumor markers is based on a high through-put immune-histochemical (IHC) screening of tumor and normal tissues using collections of murine polyclonal and mAbs raised against recombinant human proteins. In the course of such analysis, we discovered and validated different surface exposed proteins over-expressed in one or more cancers. Here, we report a surface exposed protein mainly over-expressed in ovary and breast cancers. Interestingly, the protein is highly expressed in high grade breast cancers. Approximately 40% of cancers in which the protein is over-expressed belong to the triple negative subtype. In line with IHC data, an expression profile analysis in different cells lines showed that this protein is expressed in ovarian and breast cancer cell lines. In breast cell lines, high expression was found in triple negative cells positive to the androgen receptor. Gene silencing experiments combined to phenotypic analysis, showed that loss of protein expression significantly reduces cell proliferation and invasiveness. Several mAbs able to recognize the target protein on the surface of breast and ovary cancer cell lines have been selected and validated in a number of immunoassays. The specificity of the mAb binding was confirmed by gene silencing and competition assays with peptides encompassing the mAb epitopes. Specific mAbs able to detect the protein in cancer cells in IHC are under validation. These antibodies show limited reactivity on normal human tissues and are negative on PBMC from normal donors. Moreover, these mAbs are efficiently internalized by cancer cells, suggesting that they are amenable to the development of Antibody-Drug-Conjugate. Finally, they efficiently recognize the macaca protein ortholog, thus facilitating future safety studies in non-human primates. Overall, results so far accumulated highlight the potential of this novel tumor-associated protein and available mAbs for the development of targeted therapy against ovarian cancer and triple negative breast cancer. Other promising targets and related monoclonal antibodies will be described during the meeting. Citation Format: Matteo Parri, Susanna Campagnoli, Alberto Grandi, Elisa De Camilli, Aurelien Lacombe, Boquan Jin, Serenella Eppenberger-Castori, Giuseppe Viale, Luigi Terracciano, Piero Pileri, Renata Maria Grifantini. Novel targets and monoclonal antibodies for cancer therapy. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 3800.