Abstract
e13527 Background: Monoclonal antibody represents an ideal tool to develop highly specific drugs. However, the efficacy of antibody-based drugs is strongly dependent by the effect that the protein targeted will have on the disease cell. Particularly interesting, as target for antibody therapy, are oncoantigens (OAs), i.e., surface tumor antigen that supports tumor growth. Methods: We have developed a two steps pipeline that allows identifying moAbs directed against e.g., cancer stem cells (CSC) OAs. First step: we compare transcription profiles, derived by tumor cell line grown as epithelial monolayer, with those derived by spheroids generated using the same cell line. Since spheroids are enriched in CSCs, genes up-modulated in spheroids are putative targets for antibody-targeting. Putative targets are ranked on the basis of their oncological potential and low expression in normal tissues. Top ranking targets are then tested in animal model. If vaccination inducing antibody response is able to reduce tumour growth and/or metastasis formation targets are proficient for the second step: they are used to vaccinate BALB/c mice. IgG expressing cells are isolated and libraries of the heavy (HV) and light variable (LV) chains are sequenced. Bioinformatics is then used to detect enriched VH and VL, which are transformed in single-chain antibodies to test target binding efficacy. Results: Using our pipeline we have identified, as associated to HER2+ breast cancer cell, TMPRSS4. This protein is involved in metastasis and invasion and, in hepatocellular carcinoma, it is over-expression leads to epithelial-mesenchymal transition. We are now evaluating if antibodies raised against TMPRSS4 are able to inhibit metastasis formation in BALB/c mice. On the basis of these results we will move to the second step of the pipeline. Conclusions: We have designed a pipeline that allows identification of CSC associated proteins suitable as targets for antibody-driven therapy.
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