Novel Targets for Monoclonal Antibody Therapy

The discovery of novel cancer therapeutic targets is an extremely active research field in both academia and pharmaceutical companies. In our recent research activities, we identified a group of novel candidate tumor markers for prevalent cancers, identified by a high-throughput immunohistochemistry screening of Tissue microarray (TMA) representing breast, lung colon ovary and prostate cancers. A panel of novel marker candidates were found over-expressed in one or more of the five tumors under analysis, with significant frequency. Three of them seems to be promising therapeutic targets for monoclonal antibody therapy, being exposed on the surface of cancer cells. They include: - EXN36, a lectin binding protein, over-expressed in breast, lung and ovary cancer; - EXN74, a protein involved in iron homoeostasis and over-expressed in breast, colon, lung and ovary cancers, and EXN1, a tectonic family homologous protein detected in colon, lung and ovary cancers. Gene silencing using siRNA technology and/or over-expression experiment using marker-encoding plasmids significantly alter cell proliferation, migration, invasiveness and clonal growth in vitro, indicating that expression of the three proteins confer cell phenotypes relevant for tumor progression. Highly specific murine monoclonal antibodies (mAbs) were generated against the three proteins and proved to bind the surface of cancer cells lines. Moreover, these mAbs selectively stained different cancers by IHC, where they showed cell membrane reactivity. IHC analysis conducted on TMA carrying the 35 human tissues requested by FDA showed absence of mAb cross-reactivity in any tested normal tissues indicating that the mAb targets are selectively over-expressed in malignancies. Most interestingly, current results using a mAb directed against EXN1 showed therapeutic efficacy in atymic nude mice bearing colon cancer xenografts, being able to specifically bind the tumor and significantly reduce tumor growth. This antibody could be developed as a novel tool for targeted anti-cancer antibody therapy.